Brain Organoids as Emerging Platforms for Modeling Neurodegenerative Diseases: Progress, Challenges, and Future...

Neurodegenerative diseases are a group of disorders (such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis) characterized by loss of function and death of neurons in different parts of the nervous system. These pathologies constitute a global burden, especially for aging populations. This circumstance leads to an increasing demand for understanding the fundamental mechanisms and development of therapeutic strategies. Conventional models, including two-dimensional cell culture and animal models, postmortem brain tissue provide an overview about neurodegenerative disorders but do not completely recapitulate cellular and molecular mechanisms of the human brain. Although three-dimensional (3D) brain organoids exhibit similar properties with physiological and pathological conditions of human brain, including interaction of neuronal, glial cells and self-organizing structure, protein aggregation, neuroinflammation, and neuronal degeneration. The integration of reprogrammed human induced pluripotent stem cells (iPSCs) with 3D brain organoid systems provides a clinical platform as a bridge between bench to bedside. Brain organoids have been used to elucidate novel insights into the molecular and genetic mechanisms underlying neurodegenerative diseases. Furthermore, brain organoids serve as a tool for in vitro disease modeling, drug screening and emergence of new treatments. Despite these clinical benefits, there are various limitations such as incomplete tissue maturation, lack of vascularization and incomplete cellular diversity in this 3D culture system. This review describes in detail the advantages and disadvantages of brain organoids usage in modeling neurodegenerative diseases from a contemporary perspective.